Abstract this proposal seeks 3 years of renewed support to determine the neural basis for heritable differences in the regulation of sensorimotor gating by dopamine (DA) activity in rats. Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is impaired in schizophrenia patients and other inherited neuropsychiatric disorders. The phenotype of deficient PPI in these disorders reflects abnormalities in brain mechanisms that regulate PPI. PPI is also impaired in rats by DA agonists e.g. apomorphine (APO) and amphetamine (AMPH) - and sensitivity to these effects appears to be genetically determined in rats, with robust and reliable innate differences across strains and substrains. Strain differences in the PPI-disruptive effects of DA agonists have large effect sizes even across common outbred strains - and reflect differences in CNS effects, and not in drug metabolism or distribution. Because the neurobiology of PPI is well understood in rats, it is possible to determine the neural basis for these inherited differences in the DA-regulation of PPI, and thereby to identify candidate substrates responsible for deficient PPI in neuropsychiatric disorders. Studies in PY 1-4 identified heritable components of PPI DA sensitivity in Sprague Dawley (SD) and Long Evans (LE) rats and their F1 and N2 progeny, building on past findings of strain differences in sensitivity to the PPI-disruptive effects of DA agonists. Studies determined that one neural basis for this phenotype is distal to DA release and D2 receptors in the nucleus accumbens core, but proximal to ventral pallidum (VP) GABA efflux, and is strongly associated with DA-stimulated G-protein activity. Studies proposed for the next 3 years will interrogate specific steps in the intracellular G-protein cAMP signaling pathway that might control heritable differences in DA agonist sensitivity in SD, LE and F1 rats. Dependent measures will include PPI as well as neurochemical (VP GABA efflux) and cellular (cFOS expression) markers of forebrain function. In total, studies will identify molecules that will be targets of strong inference for novel antipsychotic development. The potential contribution of these molecules to gating deficits in heritable brain disorders will be tested in new and existing animal models, and in ongoing studies of the genetic determinants of PPI deficits in schizophrenia. Ultimately, this project will identify neural, biochemical and genetic determinants of impaired sensorimotor gating in specific inherited brain disorders, at a level that will bring clarity to models of pathophysiology, and stimulate the development of new treatments. PUBLIC HEALTH RELEVANCE: Normal brain mechanisms suppress or "gate" the impact of irrelevant stimuli on sensory, cognitive and motor processes. In several inherited neuropsychiatric disorders, like schizophrenia and Toilette syndrome, a loss of these normally protective gating mechanisms leads to an intrusion of information that is experienced as unwanted and often distressing sensations, thoughts and movements. The main goal of this project is to use a well characterized animal model to identify the neural basis for an inherited vulnerability of these gating mechanisms, at a level that will reveal new targets for medications to restore gating and thereby reduce symptoms in neuropsychiatric disorders.